The present invention relates to cefpodoxim proxeril of formula 
e.g. described in The Merck Index, Twelth Edition, Item 1991, and more particularly to a process for the adjustment, e.g. change, of the diastereoisomeric ratio of the two existing diastereoisomers being with respect to the carbon atom attached to the oxygen of the ester group in the carboxyl ester group in position 4 of the ring system (marked with a star (*) in formula II). A diastereoisomeric ratio (B/A+B) of cefpodoxime proxetil currently on the market may be around 0.53. B is the more apolar of the two diastereoisomers. Because of different bioavailability of these individual diastereoisomers a commercial form for oral administration of cefpodoxim proxetil has to be within a defined ratio (B/A+B); otherwise such a form might not be bioequivalent. A diastereoisomeric ratio (B/A+B) of 0.5 to 0.6 has been found to be bioequivalent with a commercial form. Determination of the diastereoisomeric content of the diastereoisomers A and B in cefpodoxime proxetil may be carried out by HPLC, e.g. as described in Pharmacopeial Forum, Vol. 23, No. 4, p. 4388 ff (1997), the content of which is incorporated herein by reference, from which a diastereoisomeric ratio (B/A+B) and (A/A+B) may be calculated.
One process in the production of cefpodoxime proxetil may be carried out via acylation of 7-amino-3-methoxy-methyl-3-cephem-4-carboxylic acid-1-(isopropoxycarbonyloxy)ethylester of formula 
with activated Z-2-(methoxyimino)-2-(2-formylaminothiazol-4-yl)-acetic acid to obtain N-formylcefpodoxime proxetil of formula 
It was found that a mixture of diastereoisomers of a compound of formula I may be obtained in a diastereoisomeric ratio (B/A+B) of 0.48 to below 0.50. The reaction for splitting off the formyl group in a compound of formula I obtained to obtain cefpodoxime proxetil of formula II may have no significant influence on the diastereoisomeric ratio (B/A+B) and consequently (B/A+B) in cefpodoxime proxetil obtained may be outside of 0.5 to 0.6. Surprisingly a simple process has now be found wherein an appropriate diastereoisomeric ratio of the diastereoisomers of a compound of formula I may be obtained which may, result in cefpodoxime proxetil by splitting off the formyl group in a diastereoisomeric ratio which is 0.5 to 0.6.
In one aspect the present invention provides a process for the adjustment, e.g. change, of the diastereoisomeric ratio (B/A+B), wherein B is the more apolar of the two diastereoisomers, of a mixture of diastereoisomers of a compound of formula I, e.g. adjusting a diastereoisomeric ratio (B/A+B) to 0.5 to 0.6; the diastereoisomers being with respect with the carbon atom marked with a star in formula I, comprising treating a mixture of diastereoisomers of a compound of formula I, e.g. in an additive, e.g. a compound selected from an organic amide, an urea, an imidazolidinone or a pyrimidinone, e.g. a 10 to 50% (w/w) solution of a mixture of diastereoisomers of a compound of formula I in an additive; with alcohol, e.g. selecting the alcohol from (C1-6)alcohols; and water, e.g. treating a mixture of diastereoisomers of a compound of formula I with 3 ml to 10 ml alcohol and 10 ml to 30 ml water per gram of a compound of formula I.
A process according to the present invention may be carried out as follows:
A compound of formula I may be produced, e.g. in conventional manner and e.g. as follows: The carboxylic acid group in position 4 of the ring system of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (AMCA) which is a known compound and obtainable e.g. in conventional manner, may be esterified to obtain a compound of formula III. This may be effected e.g. in conventional manner, e.g. by reacting AMCA with a compound of formula
Xxe2x80x94CHxe2x80x94(CH3)xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94CH(CH3)2
wherein X denotes a leaving group, e.g. a conventional leaving group, such as a halogenide, e.g. an iodide; e.g. in the presence of a solvent. Esterification may be effected e.g. in a conventional solvent, e.g. an organic solvent such as ketones, e.g. acetone, e.g. in the presence of a hydrocarbon, e.g. toluene; and e.g. in the presence of a base; e.g. an amidine, such as 1,5-diazabicyclo(4,3,0)non-5-ene (DBN) and 1,8-diazabicyclo(5,4,0)undec-7-ene (DBU); or a guanidine, e.g. a linear guanidine, such as tetramethylguanidine, pentamethylguanidine, tetraethylguanidine, tetramethylethylguanidine and tetramethylbenzylguanidine or a cyclic or bicyclic guanidine, e.g. 1,5,7-triazabicyclo-(4,4,0)-dec-5-ene, and 7-methyl, 7-ethyl, 7-benzyl and 7-phenyl derivatives thereof. A compound of formula III obtained may be isolated, if desired, e.g. in conventional manner.
The nitrogen atom in position 7 of the ring structure of a compound of formula III, e.g. obtained as described above, e.g. with or without isolation, preferably without isolation, may be acylated e.g. in conventional manner. This may be effected e.g. by reaction of a compound of formula III obtained in in the esterifcation reaction, with activated Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid, e.g. including an ester and an acid halogenide, such as Z-(2-formylaminothiazol-4-yl)-methoxyimino-acetic acid chloride, e.g. in the form of a salt, e.g. a hydrochloride, including activated Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid obtainable by a Vilsmeier reaction. Vilsmeier activated Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid may be produced e.g. in conventional manner, e.g. in situ in the reaction mixture e.g. by treating Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid with phosphoroxyhalogenide, e.g. chloride, e.g. under Vilsmeier reaction conditions.
Acylation may be carried out in an organic solvent, including e.g. carboxylic acid esters, e.g. acetates, such as ethyl acetate; halogenated hydrocarbons, e.g. aliphatic, such as methylene chloride; e.g. in the presence of an amide, e.g. N,N-dimethylformamide; e.g. in the presence of pH adjustment. pH adjustment may be effected e.g. by addition of a base, such as an inorganic base, e.g. a carbonate or bicarbonate, e.g. sodium and potassium, or e.g. of an, e.g. weakly, basic anionic exchange resin, to a pH of ca. 2.5 to 8.0. A compound of formula I obtained may be isolated, e.g. in conventional manner. A mixture of diastereoisomers of a compound of formula I may be obtained in a diastereoisomeric ratio (B/B+A) of 0.47 up to below 0.5.
For adjustment, e.g. change, of the diastereoisomeric ratio of a mixture of diastereoisomers of a compound of formula I, e.g. obtained as described above, e.g. with or without isolation, preferably without isolation, e.g. a reaction mixture from acylation, e.g. as described above, may be treated with alcohol and water, e.g. in the presence of an additive, e.g. a compound which is liquid under the reaction conditions and wherein a compound of formula I may be dissolved, e.g. a compound selected from an organic amide, e.g. an amide of formic acid or acetic acid, or a cyclic amide, e.g. pyrrolidone or N-methylpyrrolidone, or an urea, e.g. tetramethylurea, or an imidazolidinone, e.g.1,3-dimethyl-2-imidazolidinone (DMEU) or a pyrimidinone, e.g.1,3dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), or a mixture of individual additives, e.g. as described above, preferably an organic amide or an urea. An additive may be added to a reaction mixture obtained in the acylation step. From a reaction mixture obtained in the acylation step, e.g. containing an additive, e.g. added after acylation reaction to the reaction mixture, a solvent used in the acylation step which is different from an additive described above may be evaporated off, e.g. keeping the main part of an additive in the evaporation residue.
A reaction mixture obtained in the acylation step or an evaporation residue as referred to hereinafter, e.g. obtainable e.g. as described above may be a solution, an, e.g. 10 to 50% (w/w) solution, of a mixture of diastereoisomers of a compound of formula I in an additive, containing e.g. water, e.g. small amounts, e.g. originating from the acylation step, and e.g. containing amounts of organic solvent, e.g. other than an additive, e.g. organic solvent as used in the esterification and/or acylation step, e.g. from trace amounts up to 30% (w/w) in respect with a compound of formula I, e.g. depending whether, or in which extent, an evaporation step is used.
A reaction mixture obtained in the acylation step, or an evaporation residue obtained as described above, may be treated with water and alcohol, e.g. adding, e.g. dropwise or e.g. by allowing to flow
an evaporation residue or a reaction mixture obtained in the acylation step to, e.g. into, a mixture of alcohol/water, or
a mixture of alcohol/water to, e.g. into, an evaporation residue or a reaction mixture obtained in the acylation step, or
an evaporation residue or a reaction mixture obtained in the acylation step to, e.g. into, alcohol; or alcohol to, e.g. into, an evaporation residue or a reaction mixture obtained in the acylation step; and adding, e.g. dropwise, water to, e.g. into, the mixture obtained; or adding the mixture obtained to, e.g. into, water.
Appropriate alcohols include e.g. (C1-6)alcohols, preferably methanol and ethanol and mixtures of individual alcohols. An appropriate amount of alcohol includes preferably an amount of 3 to 10 ml, e.g. 5 to 6 ml of alcohol per gram of a compound of formula I. An appropriate amount of water includes an amount which is greater than 5 ml, e.g. 10 to 30 ml per gram of a compound of formula I.
A compound of formula I may precipitate, e.g. in amorphous, e.g. filterable form. The diastereoisomeric ratio (B/B+A) of a mixture of diastereoisomers of a compound of formula I obtained may be dependent on the alcohol/water ratio in the mixture and may increase with increasing amounts of alcohol in respect with water. An alcohol/water ratio of about 1:1 to 1:6, preferably; 1:1.5 to 1:5 may conveniently be used to obtain a mixture of diastereoisomers wherein the diastereoisomeric ratio (B/B+A) is at least 0.5 and more.
In another aspect the present invention provides a process for the production of a mixture of diastereoisomers of cefpodoxim proxetil of formula II in a diastereoisomeric ratio (B/A+B), wherein B is the more apolar of the two diastereoisomers, of 0.5 to 0.6, the diastereoisomers being with respect with the carbon atom marked with a star in formula I, comprising producing a mixture of diastereoisomers of a compound of formula I, e.g. in a diastereoisomeric ratio of below 0.5, by acylating a compound of formula III, e.g. a mixture of diastereoisomers of a compound of formula III, e.g. produced by esterifying 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid with a compound of formula
Xxe2x80x94CHxe2x80x94(CH3)xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94CH(CH3)2
wherein X denotes a leaving group;
with activated Z-(2-formamidothiazol4-yl)-methoxyimino acetic acid,
treating a mixture of diastereoisomers of a compound of formula I in an additive e.g. a compound selected from an organic amide, an urea, an imidazolidinone or a pyrimidinone, e.g. a 10 to 50% (w/w) solution of a mixture of diastereoisomers of a compound of formula I in an additive; with alcohol, e.g. selected from (C1-6)alcohols, and water, e.g. treating a mixture of diastereoisomers of a compound of formula I with 3 ml to 10 ml alcohol and 10 ml to 30 ml water per gram of a compound of formula I; and splitting off the formyl group from the amino group attached to the thiazolyl group.
In another aspect the present invention provides a process for the production of a mixture of diastereoisomers of cefpodoxim proxetil of formula II in a diastereoisomeric ratio (B/A+B), wherein B is the more apolar of the two diastereoisomers, of 0.5 to 0.6, the diastereoisomers being with respect with the carbon atom marked with a star in formula II, characerized by the following steps
i) esterifying 7-amino-3-methoxymethyl-3-cephem-4carboxylic acid with a compound of formula
Xxe2x80x94CHxe2x80x94(CH3)xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94CH(CH3)2
xe2x80x83wherein X denotes a leaving group in the presence of a solvent, e.g. and in the presence of a base;
ii) acylating the amine group in position 7 of the ring system of a compound of formula III obtained in step i) with activated Z-(2-formamidothiazol-4-yl)-methoxyimino acetic acid, e.g. a halogenide, e.g. in the presence of a base;
iii) adding a compound selected from an organic amide, an urea, an imidazolidinone or a pyrimidinone to a reaction mixture obtained in step ii) and evaporating off a solvent used in the acylation step, and
iv) treating the evaporation residue obtained in step iii) with alcohol and water.
In a further aspect the present invention provides a process for the isolation of 7-[2-(2-formylaminothiazol-4-yl)-2-(Z)-(methoxyimino)-acetamido]-3-methoxyimino-3-cephem-4-carboxylic acid-1-(isopropoxy-carbonyloxy)-ethylester (as a diastercoisoineric mixture) of formula I; e.g. after the reaction of the compound of formula III with activated derivative of Z-2-(methoxyimino)-2-(2-formylaminothiazol-4-yl)-acetic acid in a solvent, characterised in that to the solution of the compound of formula I is added an organic amide, a urea, 1,3-dimethyl-2-imidazolidinone (DMEU) or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), the solvent is subsequently removed by evaporation and the residue of evaporation is mixed with water/alcohol.
A process according to the present invention is useful for the production of cefpodoxime proxetil in a diastereoisomeric ratio (B/A+B), wherein B is the more apolar of the two diastereoisomers, of 0.5 to 0.6. A diastereoisomeric ratio (B/A+B) of 0.5 to 0.6 of cefpodoxime proxetil, e.g. in a pharmaceutical composition, is bioequivalent to cefpodoxime proxetil, e.g. in a pharmaceutical composition, currently on the market. Cefpodoxime proxetil produced according to the present invention may thus be used in the same dosages to and in the same indications as cefpodoxime proxetil currently on the market.
In the following examples, which illustrates the invention more fully, but should in no way limit its scope, all temperatures are given in degrees Celsius.
The following abbreviations are used:
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DMF=N,N-dimethylformamide
TMG=tetramethylguanidine
AMCA=7-amino-3-methoxymethyl-3-cephem4-carboxylic acid
Determination of the diastereoisomeric content A and B in a compound of formula III, I and cefpodoxim proxetil may be carried out by HPLC, e.g. analogously, as described in Pharmacopeial Forum, Vol. 23, No. 4, p. 4388 ff (1997), from which a diastereoisomeric ratio (B/A+B) and (A/A+B) may be calculated.